Waldenstrom's macroglobulinemia (WM) is a relatively rare post-germinal center lymphoplasmacytic tumor that secretes large amounts of IgM. Although WM has some similarities to lymphoplasmacytic lymphoma and multiple myeloma, very little is known about the molecular pathogenesis of WM. Our previous results indicate that IgH switch recombination and IgH translocations are rare in WM, which together with the pleotropic lymphoplasmacytic morphology suggest that a block to IgH switching and plasma cell differentiation may contribute to the pathogenesis of this tumor. In addition, our collaborative results with R. Fonseca at the Mayo Clinic showed the following: WM tumors usually are diploid or near diploid with few karyotypic abnomalities, and IgH translocations are extremely rare. However, we have found that small interstitial deletions at 6q22 are present in at least 50% of WM tumors. These results suggest that the molecular pathogeneis of WM is more like chronic lymphocytic leukemia (CLL) than multiple myeloma (MM). We are continuing lentiviral strategies that may enable us to immortalize WM tumor cells. Finally, we are collaborators in a DCEG project to identify genetic abnormalities that occur in normal and tumor cells derived from individuals who are are members of families that have two or more individuals with WM or IgM MGUS.